Autophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment.

Hdl Handle:
http://hdl.handle.net/10147/206351
Title:
Autophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment.
Authors:
Crowley, Lisa C; Elzinga, Baukje M; O'Sullivan, Gerald C; McKenna, Sharon L
Affiliation:
Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute,, University College Cork and Mercy University Hospital, Grenville Place, Cork,, Ireland.
Citation:
Am J Hematol. 2011 Jan;86(1):38-47.
Journal:
American journal of hematology
Issue Date:
31-Jan-2012
URI:
http://hdl.handle.net/10147/206351
DOI:
10.1002/ajh.21914
PubMed ID:
21132731
Abstract:
Although Imatinib has transformed the treatment of chronic myeloid leukemia (CML), it is not curative due to the persistence of resistant cells that can regenerate the disease. We have examined how Bcr-Abl-expressing cells respond to two mechanistically different therapeutic agents, etoposide and Imatinib. We also examined Bcr-Abl expression at low and high levels as elevated expression has been associated with treatment failure. Cells expressing low levels of Bcr-Abl undergo apoptosis in response to the DNA-targeting agent (etoposide), whereas high-Bcr-Abl-expressing cells primarily induce autophagy. Autophagic populations engage a delayed nonapoptotic death; however, sufficient cells evade this and repopulate following the withdrawal of the drug. Non-Bcr-Abl-expressing 32D or Ba/F3 cells induce both apoptosis and autophagy in response to etoposide and can recover. Imatinib treatment induces both apoptosis and autophagy in all Bcr-Abl-expressing cells and populations rapidly recover. Inhibition of autophagy with ATG7 and Beclin1 siRNA significantly reduced the recovery of Imatinib-treated K562 cells, indicating the importance of autophagy for the recovery of treated cells. Combination regimes incorporating agents that disrupt Imatinib-induced autophagy would remain primarily targeted and may improve response to the treatment in CML.
Language:
eng
MeSH:
Animals; Autophagy/*drug effects/genetics; Cell Line, Tumor; DNA Damage; Doxorubicin/*pharmacology; Etoposide/*pharmacology; Fusion Proteins, bcr-abl/*biosynthesis/genetics; Gene Knockdown Techniques; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug; therapy/genetics/*metabolism; Mice; Molecular Targeted Therapy/methods; Piperazines/*pharmacology; Pyrimidines/*pharmacology; RNA, Small Interfering/administration & dosage/genetics; Transfection
ISSN:
1096-8652 (Electronic); 0361-8609 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorCrowley, Lisa Cen_GB
dc.contributor.authorElzinga, Baukje Men_GB
dc.contributor.authorO'Sullivan, Gerald Cen_GB
dc.contributor.authorMcKenna, Sharon Len_GB
dc.date.accessioned2012-01-31T16:39:39Z-
dc.date.available2012-01-31T16:39:39Z-
dc.date.issued2012-01-31T16:39:39Z-
dc.identifier.citationAm J Hematol. 2011 Jan;86(1):38-47.en_GB
dc.identifier.issn1096-8652 (Electronic)en_GB
dc.identifier.issn0361-8609 (Linking)en_GB
dc.identifier.pmid21132731en_GB
dc.identifier.doi10.1002/ajh.21914en_GB
dc.identifier.urihttp://hdl.handle.net/10147/206351-
dc.description.abstractAlthough Imatinib has transformed the treatment of chronic myeloid leukemia (CML), it is not curative due to the persistence of resistant cells that can regenerate the disease. We have examined how Bcr-Abl-expressing cells respond to two mechanistically different therapeutic agents, etoposide and Imatinib. We also examined Bcr-Abl expression at low and high levels as elevated expression has been associated with treatment failure. Cells expressing low levels of Bcr-Abl undergo apoptosis in response to the DNA-targeting agent (etoposide), whereas high-Bcr-Abl-expressing cells primarily induce autophagy. Autophagic populations engage a delayed nonapoptotic death; however, sufficient cells evade this and repopulate following the withdrawal of the drug. Non-Bcr-Abl-expressing 32D or Ba/F3 cells induce both apoptosis and autophagy in response to etoposide and can recover. Imatinib treatment induces both apoptosis and autophagy in all Bcr-Abl-expressing cells and populations rapidly recover. Inhibition of autophagy with ATG7 and Beclin1 siRNA significantly reduced the recovery of Imatinib-treated K562 cells, indicating the importance of autophagy for the recovery of treated cells. Combination regimes incorporating agents that disrupt Imatinib-induced autophagy would remain primarily targeted and may improve response to the treatment in CML.en_GB
dc.language.isoengen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshAutophagy/*drug effects/geneticsen_GB
dc.subject.meshCell Line, Tumoren_GB
dc.subject.meshDNA Damageen_GB
dc.subject.meshDoxorubicin/*pharmacologyen_GB
dc.subject.meshEtoposide/*pharmacologyen_GB
dc.subject.meshFusion Proteins, bcr-abl/*biosynthesis/geneticsen_GB
dc.subject.meshGene Knockdown Techniquesen_GB
dc.subject.meshHumansen_GB
dc.subject.meshK562 Cellsen_GB
dc.subject.meshLeukemia, Myelogenous, Chronic, BCR-ABL Positive/*drugen_GB
dc.subject.meshtherapy/genetics/*metabolismen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMolecular Targeted Therapy/methodsen_GB
dc.subject.meshPiperazines/*pharmacologyen_GB
dc.subject.meshPyrimidines/*pharmacologyen_GB
dc.subject.meshRNA, Small Interfering/administration & dosage/geneticsen_GB
dc.subject.meshTransfectionen_GB
dc.titleAutophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment.en_GB
dc.contributor.departmentLeslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute,, University College Cork and Mercy University Hospital, Grenville Place, Cork,, Ireland.en_GB
dc.identifier.journalAmerican journal of hematologyen_GB
dc.description.provinceMunster-

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